Merkel cell carcinoma (MCC) is a deadly neuroendocrine skin cancer that is strongly associated with environmental UV exposure. MCC is diagnosed in 1500 persons each year in the United States and has twice the disease-specific mortality of malignant melanoma. Interestingly, about 15% of MCCs are not associated with chronic sun damage, and these MCC cases occur in a younger patient population. Based on what is known from melanoma, comparative study of these MCCs of different etiology is likely to be informative. Recently, a new virus (Merkel cell polyomavirus, MCPyV) was described in MCC tumors. Based on homology to viruses that cause cancer in animals, MCPyV probably contributes to some MCC. However, 20% of MCCs do not have detectable MCPyV. In Aim 1 we will test our collection of 150 extensively annotated MCC tumors for MCPyV. We will compare clinical outcomes of MCPyV + and - tumors and investigate the relationship between MCPyV and UV. It is possible that MCPyV may substitute for mutational events induced by UV, so we hypothesize that sun-protected MCCs are more likely to be virus +. Directed studies into MCC have not identified the underlying pathogenetics. We have performed an unbiased, genome-wide screen and identified several genes potentially acting as oncogenes in MCC. To confirm and refine this list, in Aim 2 we will perform array based DNA and expression analysis on 50 more MCC tumors. This will be the largest study of MCC genetics to date, and we will further mine this data set to examine differences between MCPyV positive and negative tumors. In Aim 3 we will test the functional capabilities of 2 or more putative MCC oncogenes by classic cell culture assays of growth, invasion, and transformation. At least 1 viral and 1 cellular gene will be tested. Our proposed studies are likely to provide key pathogenetic information required for the future development of therapies targeted to this poorly understood, lethal skin cancer. This project directly links the clinic with basic biology and is well suited for training the applicant for a career as a physician scientist. PUBLIC HEALTH RELEVANCE: Merkel cell carcinoma (MCC) is a very lethal skin cancer associated with sun exposure and a newly discovered virus. There are no good treatments for metastatic MCC and MCC kills 500 people a year in the United States. The genetic changes that cause Merkel cell cancer are not well known. Learning more about what goes wrong in MCC will give us a better understanding of how sun exposure causes MCC and how we might design targeted treatments in the future.